Selective hydrodehalogenation method

ABSTRACT

The invention concerns a selective hydrodehalogenation method characterised in that it comprises a step which consists in contacting a substrate including a sp 3 hybridisation carbon atom bearing an electro-attracting group and at least a fluorine atom, and a halogen atom heavier than fluorine, with a reagent comprising: an aqueous phase, a base, a group VIII metal as hydrogenation catalyst, and hydrogen dissolved in the aqueous phase, at a concentration in equilibrium with a gas phase whereof the partial pressure in hydrogen is not less than 50 kPa, advantageously ranging between 50 kPa and 2.10 7 Pa. The invention is applicable to organic synthesis.

This application is an application under 35 U.S.C. Section 371 ofInternational Application Number PCT/FR99/03031 filed on Dec. 07, 1999.

A subject matter of the present invention is the hydrogenolysis of heavyhalogen carried by a carbon itself carrying at least one fluorine atom.

A more particular subject matter of the present invention is a processfor producing compounds carrying a fluoro atom and a hydrogen atom on acarbon of sp³ hybridization, said carbon itself carrying anelectron-withdrawing functional group. The present invention relatesmore particularly to a liquid-phase process.

Fluorinated derivatives of aliphatic nature, that is to say fluorinatedderivatives in which the fluorine is carried, at least in part, by ansp³ carbon, are generally obtained by an exchange of fluorine withanother halogen atom. This exchange is generally carried out by usinghydrofluoric acid or else salts of hydrofluoric acid.

However, one of the problems encountered is that it is often difficultto carry out the exchange between the fluorine and a halogen with ahigher atomic number when the halogen to be exchanged is carried by acarbon itself carrying a hydrogen atom.

This is why it is rather difficult to obtain compounds where analiphatic compound carries both a hydrogen and at least one fluorine.One of the routes provided consists in dehydrohalogenating (that is tosay, in removing a molecule of hydrohalic acid to give an ethyleniccompound and then hydrogenating this ethylenic compound). This route isnot possible for all compounds as a hydrogen is necessarily essential inthe β position to achieve the removal of the hydrogen and the halogenwhich it is desired to remove.

Provision has been made, in patent GB 1 364 495, to synthesize certainmonohydrogenated perfluorinated compounds (Rf-H) from the correspondingiodide (Rf-I) but this use of an iodinated derivative is very expensiveand the pressure conditions disclosed in this document are very severefor kinetics which do not appear to be very high.

European patent application EP 0 726 244 discloses the reduction of avery specific cyclopropanic acid structure which, however, does notcarry an electron-withdrawing group in in addition to a chlorine and afluorine (although the acid functional group is certainly anelectron-withdrawing group, it is not, however, connected directly tothe carbon carrying the fluorine and the halogen).

Gas-route processes have also been provided (in particular EP 0 657 413A) but, in addition to the disadvantages related to the gas route, itappears difficult to obtain a high selectivity at the same time as ahigh degree of conversion.

This is why one of the aims of the present invention is to provide aliquid-phase process which makes possible the replacement of a heavyhalogen by a hydrogen, this replacement being carried out while afluorine atom is carried by the same carbon as that which carries thehalogen to be replaced by a hydrogen.

Another aim of the present invention is to provide a process of thepreceding type which is selective with respect to fluorine.

Another aim of the present invention is to provide a process of thepreceding type which is capable of giving good results with a compoundwhich does not exhibit hydrogen β to the halogen to be made to leave.

Another aim of the present invention is to provide a process of thepreceding type which is selective with respect to fluorine withoutrequiring the use of iodide.

These aims, and others which will become apparent subsequently, areachieved by means of a selective hydrodehalogenation process (that is tosay, the operation which consists in removing the halogen from amolecule by treating the latter by means of hydrogen to give, on the onehand, hydrohalic acid and, on the other hand, the starting moleculemodified by the replacement of a halogen by a hydrogen) which comprisesa stage in which a substrate exhibiting a carbon atom of sp³hybridization carrying:

at least one electron-withdrawing group (EWG) (that is to say, a groupwith a positive Hammett constant σ_(p) or σ_(i)),

at least one fluorine atom,

and at least one halogen atom heavier than fluorine;

is brought into contact with a reactant comprising:

an aqueous phase,

a base,

a metal belonging [lacuna] Group VIII and to the fourth or to the sixthperiod of the Periodic Table as hydrogenation catalyst,

and hydrogen dissolved in the aqueous phase, at a concentration inequilibrium with a gas phase, the hydrogen partial pressure of which isat least equal to 50 kPa, advantageously between 50 kPa and 2×10⁷ Pa.

Of course, the aqueous phase is a liquid phase.

The present invention is targeted more particularly at the case wheresaid atom of sp³ hybridization carries two fluorine atoms.

The preferred electron-withdrawing functional groups are, on the onehand, optionally substituted aryls and, on the other hand, those forwhich the Hammett constant σ_(p) is at least equal to 0.1 and it is alsopreferable for the inductive component of σ_(p), σ_(i) to be at leastequal to 0.1, advantageously to 0.2, preferably to 0.3 (for example, cf.March, “Advanced Organic Chemistry”, 3rd edition, John Wiley and Son,pages 242 to 250 and in particular Tables 4 and 5).

When there is only a single electron-withdrawing group (or functionalgroup) and a single fluorine, it is desirable for one, preferably both,conditions below to be met:

either the electron-withdrawing group exhibits a σ_(i) of greater thanor equal to 0.15, advantageously at least equal to 2, preferably to 3;

or the halogen which has to be displaced is in the allylic position of aπ bond (double, triple or aromatic bond, including carbonyl and nitrilebonds), it being possible for the π bond to belong to theelectron-withdrawing group.

Mention may be made, among the electron-withdrawing groups (EWG), of:

substituted chalcogen atoms,

aryl groups,

groups exhibiting, as atom carrying the bond connecting it to theremainder of the molecule, a carbon atom connected to at least twofluorine atoms,

chalcogens with an atomic number at least equal to that ofperfluorinated sulfur (for example SF₅);

carboxylic, sulfonic and sulfinic functional groups, that is to sayfunctional groups which derive from carboxylic, sulfonic and sulfinicacids [these functional groups can be the acid functional group proper(in the acid form or advantageously in the salified form) but alsoamides, imides and esters].

Generally, the process proceeds particularly well when theelectron-withdrawing group (EWG) corresponds to a salified acidfunctional group.

In other words, the electron-withdrawing group (EWG) is then chosen fromnegatively charged groups.

Preference is given, among the metals from Group VIII, to those of thefourth period, in particular nickel and cobalt, and more particularlynickel. In the present application, reference is made to the PeriodicTable of the Elements published in the supplement to the Bulletin de laSociete chimique de France in January 1966).

This is because the metals from the platinum group exhibit a relativelymediocre selectivity with respect to the fluorine to be removed.However, the platinum period is preferable to that of palladium.

The forms which are the most readily used in the process are the solidcatalyst forms and more particularly, for nickel and cobalt, the “Raney”forms.

The preferred catalysts are catalysts based on Raney nickel, that is tosay the catalysts for which the main active element, preferably the onlyactive element, is Raney nickel.

The substrates generally do not exhibit more than 50 carbon atoms andeven do not exhibit more than 25. However, it should be emphasized thatthe process does not exhibit the same limitations as the gas-phaseroutes and thus that the molecular mass does not have a critical nature.

To obtain a good yield and a good selectivity, it is highly desirable tocarry out the reaction while maintaining the pH at a value sufficient toionize the possible acid functional group and, more generally, at leastequal to 4, advantageously to 7, preferably to 10.

The amount of base to be introduced into the reaction medium is at leastequal to the amount necessary for the neutralization of the hydrohalicacid given off during the selective hydrodehalogenation and, ifappropriate, the amount of base necessary for the neutralization of theacid functional groups of the substrate, when the latter exhibits suchfunctional groups. It is rare for the amount of base to exceed threetimes and even twice the amount necessary for the neutralization of thehydrohalic acid given off and for the neutralization of the acidfunctional groups of the substrate.

Generally, the halogen heavier than fluorine is chlorine. In fact,chlorine is the preferred halogen not from a technical viewpoint butfrom an economic viewpoint. The choice of chlorine renders theselectivity of the hydrodehalogenation more difficult with respect tothe fluorine. The present invention is of little advantage in the caseswhere the halogen is iodine; this is because the selectivity betweenfluorine and iodine is such that the effect of the present process isless marked than in the case of bromine and a fortiori of chlorine.

The hydrodehalogenation reaction is advantageously carried out at atemperature of between ambient temperature (approximately 20° C.) andapproximately 150° C. In the present description, the term“approximately” is employed to emphasize the fact that the values whichfollow it correspond to values which have been mathematically roundedoff and in particular that, when the figure or figures the furthest tothe right of a number are zeros, these zeros are positional zeros andnot significant figures, unless, of course, it is otherwise specified.In general, it is preferable to carry out the hydrodehalogenation at atemperature of between 30° C. and 100° C. (two significant figures).

The bases do not need to be completely soluble in the reaction medium.It is sufficient for them to be slightly soluble and for them tomaintain the pH at the desired values.

Mention may in particular be made of oxides and basic salts of alkalimetals or of alkaline earth metals, and the corresponding hydroxides.

Organic bases can also be used, either alone or to facilitate thetransfer of the OH⁻/H⁺ ions. Mention may be made, among the latter, ofammonium hydroxides or primary, secondary or tertiary amines. Use mayalso be made of other phase transfer agents, in particular “cryptants”,such as crown ethers.

When organic bases are used to facilitate the action of a base of lowsolubility (in particular an inorganic base), they can be used at alevel of approximately 0.1 times the amount of substrate expressed inmoles (or more generally in equivalent). In the case of the joint use ofan inorganic base and of an amine, it is pointless for the amount ofamine to be greater than 0.4 times the amount of substrate expressed inequivalent. The preferred amines are those which cannot be easilyalkylated and in particular tertiary amines.

It may be advantageous to provide a third solvent to help the substrateto be at least partially soluble in the aqueous phase.

It is preferable to choose, as third solvent, one of the solvents whichare miscible, partially or preferably in any proportion, with Water butis less polar than the latter.

It is preferable for these solvents not to be capable of beinghydrogenated under the reaction conditions. This restriction can resultin the exclusion in particular of ketones and nitriles or in the choiceof mild conditions.

Consequently, among the solvents which may be envisaged, mention shouldbe made of ethers, alcohols and their mixtures.

More generally, it is desirable for the constituents of the reactionmixture and in particular the substrate not to comprise a functionalgroup capable of being hydrogenated under the reaction conditions.

The substrates correspond in general to the following general formula:

EWG-CFX-Y

where X represents a halogen of a higher rank than that of fluorine(that is to say, essentially chlorine and bromine, preferably chlorine);

where Y represents a hydrogen (but this is not the preferred value), ahalogen atom (advantageously a fluorine), an advantageouslyelectron-withdrawing carbonaceous radical or even anelectron-withdrawing group (as defined in the present description and inparticular below);

where EWG represents an electron-withdrawing group, the possiblefunctional groups of which are inert under the reaction conditions.

The total carbon number of the substrate advantageously being within theclosed range 1 to 15, preferably 2 to 10 (apart from the carbonaceouspart of the amide, imide or ester functional groups, when the substratesare acids in one of the above forms).

Y is advantageously:

fluorine

if it is desired to obtain a monofluorinated methyl (—CH₂F), Y can havethe same values as X with the same subpreferences

a residue of formula (II) R—(CΞ₂)_(p−)

where the Ξ groups, which are alike or different, represent a fluorineor a perfluorinated radical of formula C_(n)F_(2n+1) with n an integerat most equal to 8, advantageously to 5;

where p represents an integer at most equal to 2;

where R is a hydrogen atom, a fluorine atom or a hydrocarbonaceousradical, advantageously an alkyl or aryl radical.

It is desirable for EWG to be chosen from:

aryls in which the nucleus is advantageously depleted in electron(homocycle carrying an electron-withdrawing functional group or6-membered heterocycle);

acid functional groups (that is to say, carrying acidic hydrogen,advantageously for which the pKa is at most equal to 7, preferably to4); it is advisable to choose the acid functional groups from those inwhich the proton is carried by a metalloid, advantageously by achalcogen atom, preferably by an oxygen atom;

an alkyloxyl radical; in this case, EWG advantageously corresponds tothe formula

—O—(CH_(2−m)Ξ_(m))_(p)—R (cf. below).

It is thus advantageous for EWG to correspond to the formula (III) —Z—Hor —Z⁻, in which Z represents a bivalent radical advantageously chosenfrom —C(O)—O—; —S(O)—O—; —S(O)₂—O⁻.

Mention may more particularly be made, among the preferred substrates,of carboxylic acids mono- or bifluorinated on a carbon atom carrying thecarboxylic functional group and, in particular, those in which the acarbon is both chlorinated and fluorinated.

Mention may also be made of aralkyls in which the carbon in the benzylposition is fluorinated and chlorinated.

Finally, mention may be made, as substrates exhibiting a specific natureand a particular advantage, of ethers, at least one of the carbons ofwhich which carry the ether functional group is both chlorinated andfluorinated, in which EWG corresponds to the formula:

—O—(CH_(2−m)Ξ_(m))_(p)—R

where the groups, which are alike or different, represent a fluorine ora perfluorinated radical of formula C_(n)F_(2n+1) with n an integer atmost equal to 8, advantageously to 5;

where p represents an integer at most equal to 2;

where the m values, which are alike or different, represent zero or aninteger at most equal to 2;

where R is a hydrogen atom, a fluorine atom or a hydrocarbonaceousradical of at most 10 carbon atoms, advantageously an alkyl or arylradical.

The values of m, of X and, when p is equal to 1, of R are advantageouslychosen so that the link carrying the oxygen exhibits at least onehydrogen atom and one fluorine atom; this can be advantageous inparticular during the synthesis of anesthetic ethers, such asdesflurane.

The process is particularly advantageous for substrates not exhibitinghydrogen β to the halogen to be hydrodehalogenated (see the presentationof the problem in the introductive part).

The substrate can, but this is only rarely of advantage, compriseseveral sites of EWG-CFX-type, in which case the various X groups willbe simultaneously replaced by hydrogen.

The process has proved to be particularly advantageous for fluorinatedcarboxylic acids in which the α carbon is chlorinated, in particularchloro-difluoroacetic acid, which makes it possible to obtaindifluoroacetic acid.

These carboxylic functional groups which have been spoken of previouslyare advantageously used in the form of salts, generally alkaline salts,of acid.

However, they can be used in other forms, in particular the functionalgroups derived from the acids which were mentioned above (for example,ester, imide or amide).

The stoichiometry of the reaction is:

EWG-CFX-Y+H₂→HX+EWG-CFH-Y

and, when Y is chosen from the values of X:

EWG-CFX-Y+2H₂→HX+HY+EWG-CFH₂

The following nonlimiting examples illustrate the invention:

EXAMPLE 1

57 g of water are introduced into a 300 ml Sotelem reactor made ofHastelloy HB2, stirring is begun and 57 g of chlorodifluoroacetic acid(0.44 mol) are added while cooling. 137 g of a 10N aqueous sodiumhydroxide solution (approximately 1.2 mol) are introduced, still whilecooling. 1 g of Raney nickel is subsequently added. The reactor isclosed and purging is carried out with nitrogen, with 2 times 10 bar,and with hydrogen, with 2 times 10 bar.

The reactor is placed under a pressure of 20 bar and heating is carriedout at 70° C. while stirring. The reactor is kept under constantpressure of 20 bar. When hydrogen consumption ceases, these conditionsare maintained for a further 15 min and then the reactor is cooled to20° C.; the hydrogen consumption is then substantially equal to thestoichiometric amount. Purging is carried out with nitrogen, with 2times 10 bar.

The catalyst is filtered off. By analysis of the reaction medium byion-exchange chromatography, a DC of 99.8% is obtained with a sodiumdifluoroacetate RY of 98.7%.

COMPARATIVE EXAMPLE 2

The reaction is carried out as in Example 1 but using, as catalyst, 0.50g of Pd/C comprising 5% of palladium. The results are as follows:Hydrogen consumption=approximately 50% of the SA (that is to say,Stoichiometric Amount):

DC=25%

RY_(sodium difluoroacetate)=12%

CY=50%

RY_(sodium acetate)=10%

COMPARTIVE EXAMPLE 3

The reaction is carried out as in Example 1 but dispensing with thesodium hydroxide. The results are as follows:

Hydrogen consumption=approximately 10% of the SA (that is to say,Stoichiometric Amount):

DC<10%

Presence of a significant amount of fluorine ion

Presence of acetic acid

Presence of nickel fluoride

Presence of a very small amount of DFA (difluoro-acetatedifluoroacetic).

What is claimed is:
 1. A selective hydrodehalogenation process,comprising the step of contacting a substrate of the formula; of theformula: EWG-CF₂H wherein X represents a halogen atom heavier thanfluorine and EWG represents an electron-withdrawing group inert underthe reaction conditions, with a reactant comprising an aqueous phase, abase, a metal from Group VIII and from of the fourth or the sixth periodof the Periodic Table, and hydrogen dissolved in the aqueous phase, at aconcentration in equilibrium with a gas phase, at a hydrogen partialpressure at least equal to 50 kPa to produce a product of the formula:EWG-CF2H wherein EWG is defined above.
 2. A process according to claim1, wherein the hydrogen partial pressure is between 50 kPa and 2×10⁷ Pa.3. A process according to claim 1, wherein the electron-withdrawinggroup is an aryl, a carboxylic group, a sulfonic group, a sulfinicgroups, or an atom carrying at least two fluorine atoms.
 4. A processaccording to claim wherein 1, the electron-withdrawing group is anegatively charged group.
 5. A process according to claim 1, wherein themetal from Group VIII and from of the fourth or the sixth period of thePeriodic Table, is Nickel or Cobalt.
 6. A process according to claim 5,wherein the metal from Group VIII and from of the fourth or the sixthperiod of the Periodic Table, is in the “Raney” form.
 7. A processaccording to claim 1, wherein the metal from Group VIII and from of thefourth or the sixth period of the Periodic Table, is Raney nickel.
 8. Aprocess according to claim 1, wherein the aqueous phase is maintained ata pH value at least equal to
 4. 9. A process according to claim 1,wherein the aqueous phase is maintained at a pH value at least equal to7.
 10. A process according to claim 1, wherein the aqueous phase ismaintained at a pH value at least equal to
 10. 11. A process accordingto claim 1, wherein the substrate is an acid, the amount of base beingat least equal to the amount necessary for the neutralization of saidacid, and at least equal to the amount of a hydrohalic acid given off bythe selective hydrodehalogenation.
 12. A process according to claim 1,wherein the halogen heavier than fluorine is chlorine.
 13. A processaccording to claim 1, wherein contacting is carried out at a temperaturebetween ambient temperature and 150° C.
 14. A process according to claim13, wherein the temperature is between 30° C. and 100° C.
 15. A processaccording to claim 1, wherein the base is an alkali metal ammoniumhydroxide, an alkaline earth metal ammonium hydroxide, an alkali metalcarbonate, an alkaline earth metal carbonate, a basic salt of an alkalimetal, a basic salt of an alkali metal, an ammonium or a mixturethereof.
 16. A process according to claim 1, wherein the aqueous phasecomprises a solvent to help in dissolving the substrate, said solventbeing miscible in any proportion with water and less polar than water.17. A process according to claim 1, wherein the solvent is an ether, analcohol, or a mixture thereof.
 18. A process according to claim 1,wherein the substrate is a fluorinated carboxylic acid comprising achlorinated α carbon, an aralkyl comprising a fluorinated andchlorinated carbon in a benzyl position, or an ether comprising at leastone chlorinated and fluorinated carbon carrying an ether functionalgroup.
 19. A process according claim 1, wherein the substrate ischlorodifluoroacetic acid.